Lloyd I. Sederer, MD Blog Excerpt Biomarkers for Depression: Promise or Prime Time?

Complexity and networks.

Here's the tail end of an excerpt from a blog by  Lloyd I. Sederer, MD.Medical director, New York State Office of Mental Health:
Genetics and neuroscience rival the complexity of the physics of the universe. With genetic inheritance alone, there is hardly a single or simple pathway. Often, many genes are involved in complex diseases like diabetes and depression. The genes themselves actually vary in their form and expression (called genetic alleles). Those many genes, and their alleles, also are subject to highly-variable expression as a result of the physical and emotional environment they encounter in individual human beings -- with genes being turned on and off continuously by countless factors to which the person is exposed. And even within the specific cells that the genes send their messages to (via mRNA), ever-changing intracellular activity exerts further influence on what proteins are then synthesized that drive cellular functioning. As if that cascade were not complex enough, genes mutate. They change. Some changes are quite common and some rare, but our genes are constantly undergoing changes that may be adaptive or maladaptive to our everyday lives.

Yet science is remarkable, and by dint of effort, good luck and (often accidental) discovery our species enjoys vastly greater health and life prospects than our ancestors. But brain biomarkers are not what distressed patients and families should invest in right now as they seek better diagnosis and treatment of depression. Careful clinical assessment, systematically-developed and followed treatment plans created between patient and doctor, ongoing monitoring, and course corrections when needed remain the state of the art and science. That is how the predominance of people with depression today can improve and experience greater pleasure, purpose and productivity.

To read the full-blown blog post, go to:

http://www.huffingtonpost.com/lloyd-i-sederer-md/depression-biomarkers_b_2720412.html?utm_hp_ref=health-news&ir=Health%20News

The Insatiable Desire to Understand Risk

Although uncertainty and doubt are often discussed in OCD studies, I have found that there is also a wealth of material in business and science books. Here are three good 'uns.

The Nature of Risk by Justin Mamis

"Sometimes the biggest risk of all is taking one, and the need to be sure you are making the right choice actually increases the risk. The market is not efficient and hedging doesn't work. To rely on charts to understand the market is Mamis' way. The author is an excellent market technician who offers sound financial guidance and insights into the prepared mind. He gets your thinking going with a comfortable investment philosphy that will often go against convention. There are enough anecdotes, war stories, and charts to make for sound advise. The path to market freedom is technique, and you don't have to be one of the best traders to succeed with experience. It seems to me that the entire 1990s have confirmed the ambiguities of market language and how to operate in such a world. You will know how to keep risk at bay which most of us find not to be an easy task."

Complexity, Risk, and Financial Markets by Edgar E. Peters

"A groundbreaking look at complexity theory and its implications in the world of finance

Complexity theory tells us that processes with a large number of seemingly independent agents-such as free markets-can spontaneously organize themselves into a coherent system. In this fascinating book, Edgar Peters brings together scientific theory, the artistic process, and economics to show how the randomness and uncertainty of complexity theory can be applied to financial markets. Written in an engaging and accessible style, this is a thoughtful, conceptual look at the way free markets are, by their nature, continually evolving complex systems. Expanding on previous explorations of chaos theory, Peters draws on real-life examples ranging from the Asian crisis to America's love of conspiracy to show that complexity and randomness are necessary for the free markets to operate in a competitive manner."

When in Doubt, Make Belief: An OCD-Inspired Approach to Living with Uncertainty by Jeff Bell 

"When in doubt, make belief . For author and news anchor Jeff Bell, these are words to live by. Literally. As someone who has spent much of his life battling severe obsessive compulsive disorder (OCD), Bell has had to overcome crippling uncertainty few people can imagine. In this powerful follow-up to his critically acclaimed memoir, Rewind, Replay, Repeat , Bell expounds on the principles of applied belief that allowed him to make such a remarkable recovery from this “doubting disease” and the lessons he’s learned while traveling the country talking about doubt. With the help of more than a dozen leading experts, Bell offers readers practical techniques for pushing through the discomfort of uncertainty — whether it stems from OCD or just everyday worries — and demonstrates how a shift from decisions based on fear and doubt to ones based on purpose and service can transform any life."

Of Complexity and Tipping Points: Uncertainty and the “Low Seratonin” Model

Continuing on with another entry in my OCD-themed blogging, with reports from Shadow Syndromes, by John Ratey M.D. and Catherine Johnson, Ph.D., I will now share some of their key points about the complex relationship between the brain and medication (also known as drugs).

As the authors put it, “The first point to absorb as we set about attempting to influence the course of our own biology is that the brain is infinitely complex. It is a widely accepted view among neuroscientists that the brain is the most complex system in the known universe. A quart-sized mass of tissue, the brain contains roughly 100 billion neurons, each and every one of those 100 billion neurons possessing an average of 10,000 links to other neurons. For all practical purposes, the brain is infinite.” Cue the awe-inspiring Carl Sagan voiceover.

Sadly, as usual, it seems there is no sure one-stop cure using a pharmacological magic bullet. It turns out, the oft-cited, simple-to-explain explanation of a “low” serotonin/(neourotransmitter of your choice) level is, as I felt all along in my OCD-rattled brain, actually extraordinarily complex, more complex than I, like you, was told. It seems there are unlucky 13 or more different kinds of serotonin receptors found in animals, while it is still unknown how many more serotonin receptors we humans possess. Whatever the number, each and every one of these receptors exists within each synapse and when a “serotonin-raising” medication hits the synapse, each different serotonin receptor is affected in a different way. Some receptors alter electrical transmission in response to the drug, other receptors alter chemical transmission, and so on.

Continuing with this intellectual buzz-kill of the simple solution, “But the real story of serotonin levels isn’t told by even the individual synapses being affected, because each and every synapse is always affected in turn by the neurons lying ‘downstream.’ ‘Downstream’ neurons are neurons lying past the neuron being treated by the SSRI – the neurons being ‘fed into’ by the neuron responding to the drug. The downstream neuron may feedback into the upstream neuron and actually decrease serotonin release – or the downstream neuron’s feedback may increase serotonin release further – we simply do not know, at least yet (written in 1997).”

But wait -- that’s not all -- you also get this further ungainly wrinkle, “Then you have to take the cascade of enzymes that make up the serotonin molecule into account: these enzymes may be influenced by the feedback loop as well, and the enzymes are in turn affected by ever smaller hormones like peptides and the chemistry that guides them, and we have yet to even mention genes and cell functioning.”

In short, the workings of the serotonin system are unknown. The scientists at Eli Lilly, manufacturer of Prozac, simply do not know what Prozac does to the brain downstream. They know what it does in the synapse; they do not know what the cascade of feedback loops and genetic mechanisms this synaptic change sets off.

A cascade effect is set off.  Any treatments of any kind will produce effects unique to each individual. No doctor, no psychiatrist can predict what affect this pill, or this “talking cure,” will have upon this person’s biology. The clinician can only rely on statistical averages: how many patients with this cluster of issues typically respond to a particular treatment? After that it is simply a matter of trying the treatment and seeing what happens. (Perhaps to soften this unsettling new from OCD’s two fellow travelers, Mr. Uncertainty and Mr. Risk, the authors parenthetically add: In fact, the majority of patients who choose to take up medication do end up experiencing very real and significant improvement. At least half, and probability more, of all patients who consult a psychiatrist will find the help they need). Of course that means that nearly half don’t, adds Mr. Glass Half-Empty, glumly.

A discussion of cascades, non-linear phenomena, complexity, the popular Chaos metaphor of “the butterfly effect,” and self-organizing emergence, and ensues. This is enlivened with illustrations from Malcolm Gladwell’s popular Tipping Point book.

So, the disturbing news is that the science behind the drugs is so complex, that like the weather, it is nigh-impossible to get precise, predictable forecasts about will happen when you take any neurotransmitter-enhancing medication. Minuscule changes at one location can percolate through the system so as to bring about major effects somewhere else.

The hopeful news the authors ask us to take away is that it is possible to have a positive “tipping point” as well as a negative one. It’s not a one-way street like entropy. You might be able to “tip” from the serious classic version of a disorder to a shadow syndrome, which while not perfect, will certainly bring about a welcome higher quality of life. As Mr. Gladwell put it, “it is the nature of nonlinear phenomena that sometimes the most modest of changes can bring about enormous effects.”

The authors’ musings on complexity conclude with, “Thus the notion that things might naturally come together – might naturally, inevitably and suddenly cohere; this is something new under the sun. It is such a novel concept that some complexologists believe a fifth fundamental force (in addition to gravity, electromagnetism, and the strong and weak forces that govern the atom) will be discovered to exist in nature. We are looking to tip up; we are hoping to reach that magic moment when life and love ‘self-organize’ into something splendid. That is the hope.”

Ah yes, uncertainty, risk, exposure, and hope – “Welcome back my OCD friends, to the show that never ends.”